The last several years has seen a profound increase in the use of cocaine and cocaine-related mortality in the Unites States. Clinical and pathological reports indicate that much of the toxicity associated with cocaine use results from the actions of this drug on the cardiovascular system. The mechanism(s) responsible for the cardiovascular effects of cocaine remain largely unknown. However, it is widely accepted that many of these responses result from a cocaine-mediated increase in central sympathetic outflow. This belief has recently been challenged by studies in anesthetized and decerebrate preparations which show that cocaine may actually inhibit central sympathetic outflow. Therefore, the overall goal of this application is to characterize the effects of cocaine on the central sympathetic nervous system in conscious and anesthetized rats, with special attention being paid to the brain stem sites and mechanisms involved. Three main strategies will be used in these studies. The first studies will characterize the spectrum of arterial pressure, heart rate and sympathetic nerve responses elicited by cocaine in conscious and anesthetized rats. Second, specific monoaminergic antagonists will be microinjected into the rostral ventrolateral medulla (RVLM), rostral ventromedial medulla (RVMM) and caudal raphe nuclei in an effort to block the sympathetic nerve and cardiovascular responses elicited by cocaine. Third, electrophysiological single unit recording techniques will be used to identify and characterize individual neurons in RVLM, RVMM and the raphe nuclei with activity related to sympathetic nerve discharge and/or the cardiac cycle. The effect of intravenously administered cocaine on the discharges of these sympathetic neurons will be tested. Iontophoretic application of specific antagonists onto these neurons will be used to identify the mechanism(s) (monoaminergic and/or local anesthetic) responsible for the effects of cocaine on these neurons. Successful completion of these studies will provide new and important information regarding the central sites and mechanisms involved in mediating the effects of cocaine on the sympathetic and cardiovascular systems in conscious and anesthetized rats. These studies will also provide the first characterization of sympathetic neurons in RVMM and the caudal raphe nuclei. Finally, a new and useful model will be developed to study the sympathetic and cardiovascular effects of sympathomimetic agent such as amphetamine in conscious and anesthetized rats.